Proposed Special Review Decision PSRD2019-01, Special Review for Bromoxynil and Its Associated End-use Products

Pest Management Regulatory Agency
30 January 2019
ISSN: 2561-636 (PDF version)
Catalogue number: H113-30/2019-1E-PDF (PDF version)

Web Summary

Table of Contents

• 1.0  Introduction
• 2.0  Uses of Bromoxynil in Canada
• 3.0  Aspects of the Pest Control Product that Prompted the Special Review
• 4.0  Evaluation of the Aspects of Concern that Prompted the Special Review
  • 4.1 Potential Carcinogenicity
  • 4.2 Potential Developmental Effects
  • 4.3 Characterization of the Potential Human Health Risks of Bromoxynil
  • 4.4 Characterization of the Potential Occupational Health Risks
  • 4.5 Characterization of Potential Risk to the Aquatic Environment
• 5.0 Incident Reports
• 6.0 Proposed Special Review Decision for Bromoxynil
• 7.0 Next Steps

1.0 Introduction

Pursuant to subsection 17(2) of the Pest Control Products Act, Health Canada’s Pest Management Regulatory Agency (PMRA) has initiated a special review of 3,5-dibromo-4-hydroxybenzonitrile (Canada, 2013), hereafter referred to as bromoxynil. This special review was based on the decision taken by Norway in 2000 to prohibit the use of bromoxynil octanoate (CAS No. 1689-99-2) due to human health and environmental concerns (Rotterdam Convention, 2001).

Pursuant to subsection 18(4) of the Pest Control Products Act, the PMRA has evaluated the aspects of concern that prompted the special review of pest control products containing bromoxynil. The aspects of concern for this special review are relevant to human health and the environment.

2.0 Uses of Bromoxynil in Canada

Bromoxynil is an herbicide registered in Canada for commercial use to control a wide spectrum of annual broadleaf weeds in food and feed crops including alfalfa, corn, wheat, onions, garlic, carrots, and several seedling grasses. In currently registered products, bromoxynil is present as bromoxynil octanoate, bromoxynil heptanoate, and bromoxynil phenol, and all currently registered products containing the above forms are considered in this special review. (See Appendix I of PSRD2019-01, Special Review for Bromoxynil and Its Associated End-use Products)

3.0 Aspects of the Pest Control Product that Prompted the Special Review

Based on the review of the Norwegian decision (Rotterdam Convention, 2001), the PMRA identified the aspects of concern that prompted the special review of bromoxynil as:
Human Health

• Potential carcinogenicity;
• Potential developmental effects;
• Potential occupational risk (mixer, loader, and applicator)

Environment

• Potential risk to aquatic organisms

4.0 Evaluation of the Aspects of Concern that Prompted the Special Review

Following the initiation of the special review of bromoxynil, the PMRA requested information from provinces and other relevant federal departments and agencies in accordance with subsection 18(2) of the Pest Control Products Act. In response, water monitoring data was received and was considered in the special review.

In order to evaluate the aspects of concern, the PMRA has considered all currently available relevant scientific information, which includes information submitted by registrants as part of the special review, existing reviews (Canada, 2008a; Canada, 2008b), and any relevant information obtained since 2008 (for example, available monitoring data, incident reports, Norwegian decision, and relevant information published by the European Union (European Commission, 2016) and the United States Environmental Protection Agency (USEPA) (United States, 2012; United States, 2013)).

4.1 Potential Carcinogenicity

As part of the special review, the PMRA re-assessed the potential carcinogenicity of bromoxynil based on the currently available information. In a study in Sprague Dawley rats, the liver was identified as a target organ but no treatment-related tumours were apparent at doses up to 28 mg/kg bw/day (males) or 41 mg/kg bw/day (females).

Two long-term dietary studies with bromoxynil phenol in mice were available: one conducted in Swiss mice and one conducted with higher doses in CD-1 mice. In the Swiss mouse study (1, 4 and 13 mg/kg bw/day), the combined incidence of hepatic adenomas and carcinomas in males increased in a dose-related manner. No treatment-related increased incidence of tumours was seen in female Swiss mice. In the CD-1 mouse, the combined incidence of hepatic adenomas and carcinomas in males was increased relative to control animals at every dose level tested (3, 12 and 46 mg/kg bw/day) but the dose response was not linear. An increased incidence of hepatic adenomas and carcinomas (combined) was also noted in female CD-1 mice at 53 mg/kg bw/day.

Information submitted by the registrant as part of the special review proposed a mode of action (MOA) to address the observed hepatic adenomas and carcinomas. The MOA focused on the generation of hepatocellular tumours through the activation of peroxisome proliferator-activated receptor alpha (PPARα), leading to alterations in cell growth pathways, subsequent perturbation of cell growth and survival, then selective clonal expansion of pre-neoplastic cells, and ultimately, the production of hepatic tumours.

Overall, the key events for the bromoxynil liver tumours were clear and demonstrable to support a receptor-mediated cell proliferative MOA. The strongest evidence was for a PPARα-mediated process, but the PMRA found that the influence of constitutive androstane receptor (CAR) activity could not be excluded. The dose and temporal concordance were generally acceptable for the parameters that were observed; however, there was a lack of information available to describe the onset of PPARα activation and the subsequent alteration of cell growth pathways at non-tumorigenic dose levels. Despite this shortcoming, the key events were consistently observed throughout the database and were in accordance with liver effects anticipated in a receptor-mediated cell proliferative pathway. The proposed MOA was considered biologically plausible and coherent.

However, as the role of PPARα activity could not be clearly differentiated from that of CAR, it was determined that human relevance could not be discounted on the basis of the available data. It was determined that use of a q1* for risk assessment was overly conservative given the data, and that the tumors (regardless of whether PPAR or CAR-mediated) could be addressed through a threshold approach.

The acceptable daily intake (ADI) of 0.003 mg/kg bw/day, based on a no observed adverse effect level (NOAEL) of 0.3 mg/kg bw/day, provided a margin of 1000 to the lowest tumorigenic dose of 3 mg/kg bw/day, and it is considered protective of potential carcinogenicity. Concern for potential carcinogenicity following short/intermediate-term dermal and inhalation exposures can be allayed based on the etiology of the receptor-mediated cell proliferative MOA, as tumour induction via this MOA requires a sustained proliferative response. No evidence of cell proliferation was observed in short- to intermediate-term mouse studies in the database at dose levels similar to those used for the points of departure for dermal (10 mg/kg bw/day) and inhalation (5 mg/kg bw/day) reference values. Accordingly, the dermal, and inhalation reference values are protective for any potential carcinogenicity concerns.

Overall conclusion regarding the potential carcinogenicity of bromoxynil: The PMRA review of the available toxicological database for bromoxynil determined, that bromoxynil is not mutagenic or genotoxic based on the collective data from several in vitro and in vivo tests. Bromoxynil was found to be carcinogenic in mice but not in rats. The weight-of-evidence supported a proposed receptor-mediated cell proliferative MOA for the observed bromoxynil-induced hepatocarcinogenesis in mice, and a threshold approach was deemed appropriate for characterization of potential cancer risks in humans. The reference values selected for characterization of non-cancer risks resulting from repeated exposure to bromoxynil (Appendix II of PSRD2019-01) are protective of any residual concerns regarding the oncogenic potential of bromoxynil. On this basis, a separate cancer risk assessment is not required.

4.2 Potential Developmental Effects

The PMRA reviewed the available toxicological database for bromoxynil as well as information available in the public domain (European Commission, 2016; United States, 2012) to assess potential developmental effects of bromoxynil. Developmental toxicity was evident in the database for bromoxynil phenol and bromoxynil octanoate. In rodents, the developmental effect that was most consistently observed was an increased incidence of the skeletal variation, supernumerary rib (14th rib). The rat was the most sensitive species for developmental toxicity associated with bromoxynil phenol and its octanoate form. Supernumerary ribs were the most sensitive endpoint in oral and dermal developmental toxicity studies and were considered as the point of departure for developmental toxicity. In oral studies, this effect was observed as low as 12 mg/kg bw/day (bromoxynil phenol) and 22 mg/kg bw/day (bromoxynil octanoate). In dermal developmental toxicity studies, supernumerary ribs were noted at 50 mg/kg bw/day and 15 mg/kg bw/day (bromoxynil phenol and bromoxynil octanoate, respectively). Fetal malformations were seen at higher dose levels; microphthalmia was the most consistent observation. Additional developmental effects included fusion of ribs or other skeletal structures, incomplete ossification in various areas, anophthalmia and decreases in fetal body weights. Fetal effects in rodents always occurred in the presence of maternal toxicity, which ranged from decreases in body weight and body weight gain and increased liver weights, to mortality.

In rabbits, fetal effects occurred at doses lower than those causing toxicity in maternal animals. Decreased fetal body weight, an increased incidence of supernumerary ribs and, at higher doses, malformations including microphthalmia, were repeatedly observed in oral studies with bromoxynil. At higher dose levels, mortality and abortions occurred in the dams. The lowest effect level for developmental toxicity was 15 mg/kg bw/day and was based on decreased fetal body weight and an increased incidence of supernumerary ribs. Malformations were observed at 150 mg/kg bw/day in a dermal bromoxynil phenol study; the establishment of a maternal NOAEL was precluded by dosing errors. No developmental toxicity was observed up to 80 mg/kg bw/day in a dermal study conducted with a formulation containing bromoxynil octanoate.

Overall conclusion regarding potential developmental effects of bromoxynil: Bromoxnil exposure results in developmental toxicity in animal studies. The observed increase in the incidence of supernumerary ribs in rats was considered the most sensitive endpoint of developmental toxicity. This effect was not considered a serious endpoint and occurred in the presence of maternal toxicity. Reference values were established taking into account the potential for developmental toxicity (see Appendix II, Table 1of PSRD2019-01).

Pest Control Products Act hazard characterization: For assessing risks from potential residues in food or from products used in or around homes or schools, the Pest Control Products Act requires the application of an additional 10-fold factor to threshold effects. This factor takes into account completeness of the data with respect to the exposure of, and toxicity to, infants and children, as well as potential pre- and post-natal toxicity. A different factor may be determined to be appropriate on the basis of reliable scientific data. With respect to the completeness of the toxicity database, pre-natal developmental toxicity studies in mice, rats and rabbits, a multi-generation reproduction study in rats, as well as supplemental developmental toxicity studies, were available.

No sensitivity of the young animal was noted in the reproduction study. Effects in the offspring, namely bodyweight reductions and delayed eye opening, were observed at the same level that produced bodyweight reductions in adult animals. With respect to potential pre-natal toxicity, developmental effects occurred in the presence of maternal toxicity in rats and mice. Developmental effects at the lowest doses were limited to variations (increased incidence of supernumerary ribs) or decreased fetal body weight; neither of these effects was considered a serious endpoint. Malformations, considered serious endpoints, occurred at higher doses. In rabbits, developmental effects occurred below doses resulting in maternal toxicity; these effects included variations, malformations and reduced fetal weight/size.

The increase in the incidence of supernumerary ribs in rats was considered the most sensitive endpoint of developmental toxicity. It was not considered a serious endpoint and it occurred in the presence of maternal toxicity. In consideration of this, the Pest Control Products Act factor (PCPA factor) was reduced to onefold when this endpoint was selected for risk assessment. Selection of this endpoint and the accompanying PCPA factor provides adequate margins to the malformations; it is also protective of the identified sensitivity of the rabbit fetus. For risk assessments not employing the developmental toxicity endpoint, the PCPA factor was also reduced to onefold as the selected endpoints and uncertainty factors were protective of developmental toxicity.

4.3 Characterization of the Potential Human Health Risks of Bromoxynil

To determine if risk to Canadians from exposure to bromoxynil was acceptable, the PMRA conducted scientifically-based risk assessments relative to the aspects of concern. Toxicology reference values considered for the risk assessments are outlined in Appendix II of PSRD2019-01.

When assessing health risks, the PMRA considers two key factors – the levels at which no adverse health effects occur, and the levels to which people may be exposed. The levels used to assess risks are established to protect the most sensitive human population, for example, children and nursing mothers. As such, sex and gender are taken into account in the risk assessment. Only uses for which the exposure is well below the levels that cause no effects in animal testing are considered acceptable for registration.

Exposure to bromoxynil may occur through consuming food and drinking water, working as a mixer/loader/applicator, and/or by entering treated sites to perform postapplication activities. Residential exposure to spray drift may also occur. As such, the PMRA assessed potential non-occupational (Section 4.3.1 to 4.3.3) and occupational (Section 4.4) risks resulting from exposure to bromoxynil.

4.3.1 Dietary Exposure and Risk Assessment:

Aggregate dietary risk assessment incorporates exposure from food and drinking water and the toxicity of a given pesticide. For acute and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose and is of concern when the estimated dietary risk exceeds 100% of the reference dose. The acute (ARfD) and chronic (ADI) reference doses for bromoxynil are summarized in Appendix II of PSRD2019-01.

For the purpose of the dietary risk assessment, the Canadian residue definition of bromoxynil in plants (except canola) and animals is bromoxynil. The residue definition in canola is bromoxynil plus the metabolite 3,5-dibromo-4-hydroxybenzoic acid (DBHA). The residue definition in water is bromoxynil plus DBHA. Parent and transformation products were considered to be equivalent in toxicity.

Acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model - Food Commodity Intake Database™ (DEEM-FCID™, Version 4.02) program which incorporates food consumption data from the National Health and Nutritional Examination Survey, What We Eat in America (NHANES/ WWEIA) dietary survey for the years 2005-2010, available through Centers for Disease Control and Prevention’s (CDC) National Center for Health Statistics (NCHS). The basic acute and chronic dietary assessments were performed using Canadian Maximum Residue Limits (MRLs), American tolerances for imported commodities, and default processing factors. Refinements included the use of the highest (acute) and median (chronic) field trial residues, experimental processing factors (where available), and anticipated residues in animal commodities.

Estimated environmental concentrations (EECs) for the combined residue of bromoxynil and its transformation product DBHA in potential sources of drinking water were modelled using the Surface Water Concentration Calculator (SWCC) model on a standard Level 1 scenario (a small reservoir). EECs in groundwater were calculated using the Pesticide Root Zone Model Groundwater (PRZM GW). The following Level 1 EECs were used for the drinking water input values:

• EECs for use in acute dietary exposure estimates: 32 µg a.e./L; and
• EECs for use in chronic dietary estimates: 4.7 µg a.e./L.

In addition to modelling, available groundwater and surface water monitoring data were considered by the PMRA. There were no quantifiable detections of bromoxynil in Canadian groundwater sources. Bromoxynil has been detected in surface water in the provinces of Alberta, Manitoba, Saskatchewan, Ontario, and Quebec. The Canadian data shows that the overall detection frequency is less than 50% in most studies, with maximum single concentrations in potential surface water sources of drinking water being less than or equal to 0.96 μg/L. The currently available data does not allow for a representative long term exposure value to be determined based on the monitoring information. Thus, the modelled screening level EECs were used in the dietary risk assessment for bromoxynil and are considered conservative as they are approximately 32 (acute) and 4.5 (chronic) times higher than the maximum level of bromoxynil detected in Canadian drinking water sources.

The refined acute aggregate (food plus drinking water) dietary exposure to bromoxynil and its transformation product (DBHA) at the 95th percentile is 3% of ARfD for the general population, and it ranges from 2% to 8% of the ARfD for all subpopulations (8% of the ARfD for all infants, and 4% of the ARfD for females 13-49 years old).

The refined chronic aggregate (food plus drinking water) dietary exposure to bromoxynil and its transformation product (DBHA) is 15% for the general population, and it ranges from 10% to 59% of the ADI for all subpopulations (59% of the ADI for children 1-2 years old, and, <30% of the ADI for all infants).

Based on the results of the dietary exposure assessment, the PMRA concluded that both acute and chronic dietary risks from exposure to residues of bromoxynil are considered to be acceptable for all populations under the current conditions of use. No further risk mitigation measures are proposed.

4.3.2 Residential (Non-Occupational) Exposure and Risk Assessment:

There are no registered domestic-class products containing bromoxynil; therefore, domestic handler exposure is not anticipated. Further, commercial-class products are not registered for use in residential areas. As such, dermal and inhalation exposure to individuals from handling bromoxynil or entering a treated area at home are not expected. Nonetheless, there is a potential for bystander inhalation exposure to spray drift that results from agricultural applications of bromoxynil.

Current labels have statements to mitigate spray drift to residential areas, and potential bystander exposure to spray drift is considered to be significantly lower than the inhalation exposure of an applicator, for whom the potential inhalation risks are considered to be acceptable under current conditions of use (see Section 4.4 for further details). On this basis, the PMRA concluded that the potential residential risk is considered to be acceptable for all populations under the current conditions of use. No further risk mitigation measures are proposed.

To meet the current labelling standard and for consistency, updates to standard spray drift statements are proposed to be included on current labels (Appendix V of PSRD2019-01).

4.3.3 Aggregate Assessment:

Aggregate exposure is the total exposure to a single pesticide that may occur from food, drinking water, residential, and other non-occupational sources from all known or plausible exposure routes (oral, dermal, and inhalation). For bromoxynil, aggregate exposure is limited to food and drinking water only, as the potential bystander inhalation exposure is expected to be negligible and is not considered to significantly contribute to the overall exposure to bromoxynil. As described in Section 4.3.1, aggregate dietary exposure to bromoxynil residues from food and drinking water is considered to be acceptable for all population subgroups. No further risk mitigation measures are proposed.

4.3.4 Cumulative Assessment:

The Pest Control Products Act requires that the PMRA consider the cumulative effects of pest control products that have a common mechanism of toxicity. For the current special review, the PMRA did not identify information indicating that bromoxynil shares a common mechanism of toxicity with other pest control products. Therefore, there is no requirement for a cumulative risk assessment at this time.

4.3.5 Overall Conclusion on Potential Non-Occupational Risks:

Based on the risk assessments, potential risks resulting from non-occupational exposure to bromoxynil residues are considered to be acceptable for all populations under the current conditions of use. No additional mitigation measures are proposed.

4.4 Characterization of the Potential Occupational Health Risks

Occupational risk is estimated by comparing potential exposure with the most relevant endpoint from toxicology studies to calculate a margin of exposure (MOE). This value is then compared to a target MOE which incorporates uncertainty factors protective of the most sensitive subpopulation. If the calculated MOE is less than the target MOE, it does not necessarily mean that exposure will result in adverse effects, but mitigation measures to reduce risk would be required.

Mixer/Loader/Applicator Exposure and Risk: Based on the current bromoxynil use pattern, mixer/loader/applicator (M/L/A) exposure is expected to be short-to-intermediate term and to occur via both dermal and inhalation exposure routes.

Daily exposures to workers mixing, loading, and applying bromoxynil using groundboom and aerial application equipment were estimated using exposure data from the Pesticide Handlers Exposure Database (PHED) and/or the Agricultural Handlers Exposure Task Force (AHETF). Standard assumptions included default area treated per day (ATPD) values, maximum application rates as per current labels, and an average worker body weight of 80 kg. Since the dermal reference dose for bromoxynil was based on a dermal study, a dermal absorption value was not required for the assessment. The inhalation reference dose was based on an oral study, and an inhalation absorption factor of 100% (default value) was used in route-to-route extrapolation. The assessment considered the minimum PPE as specified on some current bromoxynil product labels, as well as additional PPE when risks of concern were identified for workers under current conditions of use.

Based on the results of the risk assessment (Appendix III, Table 1 of PSRD2019-01), the PMRA determined that potential short- to intermediate-term combined (dermal + inhalation) risk for mixers/loaders/applicators using groundboom application equipment is considered to be acceptable with the use of the following additional PPE:

• Mixers/Loaders: coveralls, a long‐sleeved shirt, long pants, chemical-resistant gloves, and shoes plus socks during mixing, loading, clean‐up and repair; and
• Applicators: a long‐sleeved shirt, long pants, chemical-resistant gloves, and shoes plus socks during open-cab groundboom. Chemical-resistant gloves are not required for closed-cab groundboom application.

Certain product labels do not include the above PPE requirements. Therefore, for consistency and to improve clarity, updates to the PPE requirements are proposed.

For the aerial application scenario, the risk to aerial mixers/loaders and applicators is considered to be acceptable under current conditions of use. No additional mitigation measures are required.

Postapplication Exposure and Risk: Bromoxynil is regarded as non-volatile with a vapour pressure of 1.425 × 10-6 mm Hg at 25°C (Canada, 2008a). The volatility of this active ingredient is below the NAFTA criterion for a waiver of inhalation exposure data for outdoor uses (vapour pressure of less than 7.5 × 10-4 mm Hg; NAFTA, 1999) and, assuming at least 12 hours have passed before re-entry, inhalation exposure to bromoxynil is not expected for postapplication workers re-entering treated sites. Thus, dermal exposure is considered to be the primary route of exposure for workers entering treated fields to conduct postapplication activities, and it is expected to be short-to-intermediate term in duration.

For workers entering a treated site, restricted-entry intervals (REIs) are calculated to determine the minimum length of time required before workers can enter after application to perform tasks involving hand labour. An REI is the duration of time that must elapse in order to allow residues to decline to a level where there are no risks of concern for postapplication worker activities. Current end-use product labels specify a 24-hour REI for all uses.

Dermal exposures on the day of application (day 0) for workers entering treated sites to perform postapplication activities were estimated using activity-specific transfer coefficients (TCs) and dislodgeable foliar residues (DFRs). A transfer coefficient (TC), usually expressed in units of cm2 per hour, expresses the relationship between worker dermal exposure and dislodgeable residues found on bromoxynil-treated plants. Transfer coefficients are specific to a given crop (and crop stage) and activity combination, and they reflect standard agricultural work clothing worn by postapplication adult workers. Activity-specific TCs from the Agricultural Re-Entry Task Force (ARTF) were used in the risk assessment. In the absence of chemical-specific DFRs, default DFRs were calculated assuming a 25% deposition of bromoxynil residues following application at the maximum application rate and a10% dissipation rate of these residues per day. Additional assumptions used included an 8 hour workday and an average worker body weight of 80 kg. For crops with two applications at the maximum rate, a re-treatment interval of 10 days for onion (as per current label directions) or 21 days for sweet corn and established alfalfa (based on current use practices) was assumed. Since the dermal reference dose for bromoxynil was based on a dermal study (Appendix II of PSRD2019-01), a dermal absorption value was not required for the assessment.

The dermal risk assessment for workers performing postapplication activities in outdoor crops is presented in Table 2 of Appendix III of PSRD2019-01. The target dermal MOE of 100 was met or exceeded for all applicable crops/activities at the 24-hour REI specified on the current labels with the exception of handset irrigation (sweet corn and garlic) and hand harvesting (sweet corn). Consequently, the following REIs are proposed to be included on the current end-use products labels:

• Sweet corn, handset irrigation – 5 day REI;
• Sweet corn, hand harvesting – 20 day REI; and
• Garlic, handset irrigation – 2 day REI.

4.4.1 Overall Conclusion for Occupational Risks

Based on the occupational risk assessments, the PMRA has concluded that:

• Potential risk to workers mixing/loading and applying using groundboom equipment is not considered to be acceptable considering PPE as specified on certain end use product labels. For consistency and to improve clarity, updates to the PPE requirements are proposed, and the potential risk to workers mixing, loading, and applying bromoxynil using ground equipment is considered to be acceptable with the updated PPEs (Appendix V of PSRD2019-01);
• Potential risks to workers mixing/loading for aerial applications and to workers applying using aerial application equipment are considered to be acceptable under current conditions of use. No additional risk mitigation measures are required; and
• Potential risks to postapplication workers are considered to be acceptable for all sites/activities at the REI (24 hours) specified on current labels, with the exception of workers involved in handset irrigation (sweet corn and garlic) and hand harvesting (sweet corn). To mitigate potential risks for workers using handset irrigation (sweet corn and garlic) and hand harvesting (sweet corn), additional mitigation measures (REIs) are proposed (Appendix V of PSRD2019-01).

In addition, in order to improve clarity of the end-use product labels, specific use directions (two applications at a minimum re-treatment interval of 21 days) are proposed to be included for established alfalfa and corn. The proposed label amendments are summarized in Appendix V of PSRD2019-01.

4.5 Characterization of Potential Risk to the Aquatic Environment

As part of this special review, potential risk to non-target aquatic organisms resulting from applications of bromoxynil was assessed using available information (Canada, 2008a; Canada, 2008b; United States, 2013a; United States 2013b). When used as directed, bromoxynil can enter the environment following application to agricultural fields and grasslands. Non-target aquatic habitats may be exposed to residues of bromoxynil as a result of spray drift and/or runoff.

Bromoxynil octanoate is not expected to persist in the environment: the esters dissipate rapidly in the aerobic environment (aerobic soil biotransformation half-life = 2 days; aerobic aquatic half-life = 0.6 days) to the phenol form which further degrades to CO2. Bromoxynil octanoate is expected to be slightly mobile in soil based on its soil adsorption characteristics. If bromoxynil enters water through spray drift or runoff, it is not expected to remain as it is regarded as non-persistent in aquatic systems.

Toxicity studies indicate that bromoxynil is very highly acutely toxic to freshwater fish (bluegill sunfish LC50 = 29 µg/L), and the chronic no observed effect concentration (NOEC) in fathead minnows is 9 µg/L. With respect to freshwater aquatic invertebrates, studies suggest that bromoxynil is also very highly acutely toxic to aquatic invertebrates (Daphnia pulex EC50 = 11µg/L), and the chronic aquatic invertebrate NOEC is 2.5 µg/L (Daphnia magna). Acute studies show that bromoxynil was found to be highly toxic to estuarine/marine fish (sheepshead minnow, LC50 = 170 µg/L) and very highly toxic to estuarine/marine invertebrates (Mysid shrimp, LC50 = 65 µg/L). For aquatic algae and diatoms, the most sensitive EC50 was 51µg/L (Navicula pelliculosa), and for vascular aquatic plants (Lemma gibba), the EC50 was 219 µg/L.

Potential risk of bromoxynil to aquatic organisms: An environmental risk assessment integrates environmental exposure and ecotoxicology information to estimate the potential for adverse effects on non-target species. This integration is achieved by comparing exposure concentrations with concentrations at which adverse effects occur. Estimated environmental concentrations (EECs) are concentrations of a pesticide in various environmental media, such as water. The EECs are estimated using standard models which take into consideration the application rate(s), chemical properties, and environmental fate properties, including the dissipation of the pesticide between applications. Ecotoxicology information used to establish reference endpoints includes acute and chronic toxicity data for various organisms or groups of organisms from aquatic habitats including invertebrates, vertebrates, and plants. I

nitially, a conservative screening-level risk assessment is performed to identify pesticides and/or specific uses that do not pose a risk to non-target organisms and to identify those groups of organisms for which there may be a potential risk. The screening level risk assessment uses simple methods, conservative exposure scenarios (for example, application at a maximum cumulative application rate), and sensitive toxicity endpoints. A risk quotient (RQ) is calculated by dividing the EEC with an appropriate toxicity value (RQ = exposure/toxicity). The RQ is then compared to the PMRA’s level of concern for aquatic organisms (LOC = 1).

Screening level RQs (direct overspray to the aquatic environment) were exceeded for the aquatic risk assessment: risk quotients based on the most sensitive aquatic endpoints ranged from 1 to 25. Therefore, risk to aquatic habitats via both runoff and spray drift were characterised separately.

The EECs in water from runoff (EEC for acute risk is 10 µg a.i./L; EEC for chronic risk is 1.0 µg a.i./L ) was modeled using the Generic Estimated Environmental Concentration Program (GENEEC) (Canada, 2008a) based on conservative fate parameters and application rates. In addition, the PMRA considered the available surface water monitoring information, and, the maximum concentration of bromoxynil measured in Canadian waters (18 µg a.i./L) was compared to aquatic toxicity values. All RQs based on the concentration of bromoxynil from runoff (modelled and monitoring information) were <10. Based on the Canadian use pattern (ground and aerial application), risk to aquatic organisms from spray drift was also characterised. This assessment was based on the maximum cumulative application rate for bromoxynil on Canadian labels and deposition of pesticide residues at 1 m downwind from the site of application. For all crop/application scenarios, RQs (based on spray drift) were <2.

To minimize exposure of bromoxynil to the aquatic environment, current end-use product labels include information on best practices to minimize runoff following application as well as buffer zones (Appendix IVof PSRD2019-01) to mitigate the potential risk from spray drift. As such and based on the available information, potential risk to non-target aquatic organisms from the use of bromoxynil is considered acceptable when current label directions are followed. No further risk mitigation measures are proposed.

To meet the current labelling standard and for consistency, updates to the aquatic toxicity statement, the runoff statements, and use directions are proposed. (Appendix V of PSRD2019-01).

5.0 Incident Reports

The PMRA incident reporting database was searched for incident reports related to the identified aspects of concern for bromoxynil. As of 28 May 2018, the PMRA has received 12 human and one environmental incident report(s) involving bromoxynil which were related to the identified aspects of concern specific to occupational health risk (mixing, loading and/or applying) and the environment. No incident reports were related to carcinogenicity or developmental effects. The 12 incidents were relevant to the occupational health risk occurred in Canada. They were classified as minor in severity, and all, except one, involved other active ingredients in addition to bromoxynil. The lone incident involving only bromoxynil reported an applicator being sprayed in the face with the concentrated product. Ocular, oral, and dermal exposures were reported along with minor symptoms including pharyngolaryngeal pain, paresthesia, and nausea. All symptoms resolved within 24 hours. The other 11 occupational incidents included bromoxynil and other active ingredients with various exposure scenarios.

One environmental incident was relevant to the aquatic risk. The incident was of major severity and occurred in Canada: water used to douse a fire at a chemical distribution warehouse entered a stream and was followed by the mortality of a large number of fish. However, bromoxynil was considered unlikely to have contributed to the fish mortality as water samples contained the presence of several other pesticide ingredients, and the concentration of bromoxynil detected was not expected to have caused the fish mortality.

Overall, no human health or environmental concerns were identified in the incident reports when products are used according to current label directions. Therefore, no additional risk mitigation measures were proposed as a result of these incidents.

6.0 Proposed Special Review Decision for Bromoxynil

Evaluation of available scientific information related to the aspects of concern indicates that the potential dietary and non-occupational risks to human health and the potential risk to non-target aquatic organisms are considered acceptable under the current conditions of use. No additional risk mitigation measures are proposed. However, to meet the current labelling standard and for consistency, updates to the aquatic toxicity statement, the runoff statements, and use directions are proposed.

The assessments indicate that the potential occupational risk to workers mixing and loading for aerial application and to workers applying bromoxynil using aerial equipment are considered to be acceptable with the current label directions. No additional risk reduction measures are proposed.

The potential occupational risk to workers mixing, loading, and applying bromoxynil using groundboom equipment is not considered to be acceptable with PPE as specified on certain end use product labels. For consistency and to improve clarity, updates to the PPE requirements are proposed. Potential risk to workers mixing, loading, and applying bromoxynil using ground equipment is considered acceptable with the updated PPE.

The potential risks to postapplication workers are considered to be acceptable for all sites/activities under the current conditions of use, with the exception of workers involved in certain activities (handset irrigation in sweet corn and garlic and hand harvesting in sweet corn). Therefore, additional risk reduction measures are proposed to mitigate potential risks for workers performing handset irrigation (sweet corn and garlic) and hand harvesting (sweet corn). With the proposed additional risk reduction measures (REIs), potential risk to post application workers performing handset irrigation in sweet corn and garlic, as well as hand harvesting in sweet corn, is considered acceptable.

On this basis, Health Canada’s Pest Management Regulatory Agency, pursuant to subsection 21(1) of the Pest Control Product Act, is proposing continued registration of bromoxynil products for sale and use in Canada with additional mitigation measures. The proposed label amendments are summarized in Appendix V of PSRD2019-01.

PSRD2019-01 special review decision is a consultation document. The PMRA will accept written comments on PSRD2019-01 up to 45 days from the date of its publication. All comments are to be directed to Publications.

7.0 Next Steps

Before making a final decision on the special review of bromoxynil, the PMRA will consider all comments received from the public in response to PSRD2019-01. A science-based approach will be applied in making a final decision on bromoxynil. The PMRA will then publish a special review decision document, which will include the decision, the reasons for it, a summary of the comments received on the proposed decision, and the PMRA’s response to these comments.